Vaccine delivery compositions and methods of use

Abstract

The present invention provides synthetic vaccine delivery compositions based on polyester amide (PEA), polyester urethane (PEUR), and polyester urea (PEU) polymers for stimulating an immune response to a variety of pathogenic organisms and tumor cells in humans and other mammals. The vaccine delivery compositions are formulated as a liquid dispersion of polymer particles or molecules including class I or class II antigen peptides derived from organism or tumor cell proteins, which are taken up by antigen presenting cells of the mammal to induce an immune response in the mammal. Methods of inducing an immune response to the pathogenic organism or tumor cells in the invention compositions are also included.

1 . A vaccine delivery composition comprising: 
 an effective amount of at least one MHC class I or class II peptidic antigen conjugated to particles or molecules of a biodegradable poly(ester amide) (PEA) polymer having a chemical structure described by structural formula (I),                          wherein n ranges from about 5 to about 150; R 1  is independently selected from residues of α,ω-bis(4-carboxyphenoxy)-(C 1 -C 8 )alkane, 3,3′-(alkanedioyldioxy)dicinnamic acid or 4,4′-(alkanedioyldioxy)dicinnamic acid, (C 2 -C 20 )alkylene, or (C 2 -C 20 )alkenylene; the R 3 s in individual n monomers are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 1 -C 20 )alkyl, and —(CH 2 ) 2 S(CH 3 ); and R 4  is independently selected from the group consisting of (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene, (C 2 -C 8 )alkyloxy, (C 2 -C 20 )alkylene, a residue of a saturated or unsaturated therapeutic diol, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula (II), and combinations thereof, (C 2 -C 20 )alkylene, and (C 2 -C 20 )alkenylene;                          or a PEA polymer having a chemical formula described by structural formula (III):                          wherein n ranges from about 5 to about 150, m ranges about 0.1 to 0.9: p ranges from about 0.9 to 0.1; wherein R 1  is independently selected from residues of α,ω-bis(4-carboxyphenoxy)-(C 1 -C 8 )alkane, 3,3′-(alkanedioyldioxy)dicinnamic acid or 4,4′-(alkanedioyldioxy)dicinnamic acid, (C 2 -C 20 )alkylene, or (C 2 -C 20 )alkenylene; each R 2  is independently hydrogen, (C 1 -C 12 )alkyl or (C 6 -C 10 )aryl or a protecting group; the R 3 s in individual m monomers are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 1 -C 20 )alkyl, and —(CH 2 ) 2 S(CH 3 ); and R 4  is independently selected from the group consisting of (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene, (C 2 -C 8 )alkyloxy, (C 2 -C 20 )alkylene, a residue of a saturated or unsaturated therapeutic diol or bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula (II), and combinations thereof    or a poly(ester urethane) (PEUR) polymer having a chemical formula described by structural formula (IV),                          wherein n ranges from about 5 to about 150; wherein R 3 s in independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 1 -C 20 )alkyl, and —(CH 2 ) 2 S(CH 3 ); R 4  is selected from the group consisting of (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene or alkyloxy, a residue of a saturated or unsaturated therapeutic diol, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula (II); and combinations thereof, and R 6  is independently selected from (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene or alkyloxy, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of general formula (II), and combinations thereof;    or a PEUR polymer having a chemical structure described by general structural formula (V)                          wherein n ranges from about 5 to about 150, m ranges about 0.1 to about 0.9: p ranges from about 0.9 to about 0.1; R 2  is independently selected from hydrogen, (C 6 -C 10 )aryl(C 1 -C 20 )alkyl, or a protecting group; the R 3 s in an individual m monomer are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 1 -C 20 )alkyl and —(CH 2 ) 2 S(CH 3 ); R 4  is selected from the group consisting of (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene or alkyloxy, a residue of a saturated or unsaturated therapeutic diol and bicyclic-fragments of 1,4:3,6-dianhydrohexitols of structural formula (II) and combinations thereof; and R 6  is independently selected from (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene or alkyloxy, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of general formula (II), an effective amount of a residue of a saturated or unsaturated therapeutic diol, and combinations thereof;    or a poly(ester urea) (PEU) having a chemical formula described by general structural formula (VI):                          wherein n is about 10 to about 150; the R 3 s within an individual n monomer are independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 1 -C 20 )alkyl and —(CH 2 ) 2 S(CH 3 ); R 4  is independently selected from (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene, (C 2 -C 8 )alkyloxy(C 2 -C 20 )alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II);    or a PEU having a chemical formula described by structural formula (VII)                          wherein m is about 0.1 to about 1.0; p is about 0.9 to about 0.1; n is about 10 to about 150; each R 2  is independently hydrogen, (C 1 -C 12 )alkyl or (C 6 -C 10 )aryl; the R 3 s within an individual m monomer are independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -C 10 )aryl(C 1 -C 20 )alkyl and —(CH 2 ) 2 S(CH 3 ); each R 4  is independently selected from (C 2 -C 20 )alkylene, (C 2 -C 20 )alkenylene, (C 2 -C 8 )alkyloxy(C 2 -C 20 )alkylene, a residue of a saturated or unsaturated therapeutic diol; a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II), and combinations thereof.    or (III).    
     
     
         2 . The composition of  claim 1 , wherein the peptidic antigen comprises from 5 to about 30 amino acids.  
     
     
         3 . The composition of  claim 1 , wherein the composition is formulated as a dispersion of the polymer particles or molecules.  
     
     
         4 . The composition of  claim 1 , wherein the polymer is a PEA described by structural formula (I) or (III).  
     
     
         5 . The composition of  claim 4 , wherein at least one R 1  is a residue of α,ω-bis(4-carboxyphenoxy)(C 1 -C 8 )alkane, 3,3′-(alkanedioyldioxy)dicinnamic acid, or 4,4′(alkanedioyldioxy)dicinnamic acid, or at least one R 4  is a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II).  
     
     
         6 . The composition of  claim 4 , wherein at least one R 1  is a residue of α,ω-bis(4-carboxyphenoxy)(C 1 -C 8 )alkane, 3,3′-(alkanedioyldioxy)dicinnamic acid, or 4,4′-(alkanedioyldioxy)dicinnamic acid, or a mixture thereof, and at least one R 4  is a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II).  
     
     
         7 . The composition of  claim 1 , wherein the polymer is a PEUR described by structural formula (IV) or (V).  
     
     
         8 . The composition of  claim 7 , wherein at least one R 1  is a residue of α,ω-bis(4-carboxyphenoxy)(C 1 -C 8 )alkane, 3,3′-(alkanedioyldioxy)dicinnamic acid, or 4,4′-(alkanedioyldioxy)dicinnamic acid, or at least one R 4  is a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II).  
     
     
         9 . The composition of  claim 7 , wherein at least one R 1  is a residue of α,ω-bis(4-carboxyphenoxy)(C 1 -C 8 )alkane, 3,3′(alkanedioyldioxy)dicinnamic acid or 4,4′(alkanedioyldioxy)dicinnamic acid, or a mixture thereof, and at least one R 4  is a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II).  
     
     
         10 . The composition of  claim 1 , wherein the polymer is a PEU described by structural formula (VI) or (VII).  
     
     
         11 . The composition of  claim 10 , wherein at least one R 1  is a bicyclic-fragment of a 1,4:3,6-dianhydrohexitol of structural formula (II).  
     
     
         12 . The composition of  claim 1 , wherein the composition forms a time release polymer depot when administered in vivo.  
     
     
         13 . The composition of  claim 1 , wherein the composition biodegrades over a period of twenty-four hours, about seven days, about thirty days, or about 90 days.  
     
     
         14 . The composition of  claim 1 , wherein the composition is in the form of particles having an average diameter in the range from about 10 nanometers to about 1000 microns and the at least one peptidic antigen is dispersed in each polymer molecule of the particles.  
     
     
         15 . The composition of  claim 14 , wherein the particles further comprise a covering of a polymer.  
     
     
         16 . The composition of  claim 1 , wherein the particles have an average diameter in the range from about 10 nanometers to about 10 microns.  
     
     
         17 . The composition of  claim 1 , wherein a particle includes from about 5 to about 150 peptidic antigens per polymer molecule.  
     
     
         18 . The composition of  claim 1 , wherein a polymer molecule has an average molecular weight in a range from about 5,000 to about 300,000 and the at least one peptidic antigen is conjugated to the polymer molecule.  
     
     
         19 . The composition of  claim 1 , wherein a polymer molecule has from about 5 to about 70 peptidic antigens conjugated thereto.  
     
     
         20 . The composition of  claim 1 , wherein the polymer is contained in a polymer-antigen conjugate having a chemical structure of structural formula (VIII):  
       
         
           
           
               
               
           
         
       
       wherein n, m, p, R 1 , R 3 , and R 4  are as above, R 5  is selected from the group consisting of —O—, —S—, and —NR 8 —, wherein R 8  is H or (C 1 -C 8 )alkyl; and R 7  is the peptidic antigen.  
     
     
         21 . The composition of  claim 20 , except that two or more molecules of the polymer are crosslinked to provide an —R 5 —R 7 —R 5 — conjugate.  
     
     
         22 . The composition of  claim 20 , except that the antigen is covalently linked to one molecule of the polymer through the —R 5 —R 7 —R 5 — conjugate and R 5  is independently selected from the group consisting of —O—, —S—, and NR 8 —, wherein R 8  is H or alkyl. (Formula (IX).  
     
     
         23 . The composition of  claim 21 , except that R 1  is independently (C 2 -C 20 )alkylene or (C 2 -C 20 )alkenylene, and wherein one of R 5  is —X—Y—, wherein X is selected from the group consisting of (C 1 -C 18 )alkylene, substituted alkylene, (C 3 -C 8 )cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted heterocyclic, (C 2 -C 18 )alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 6  and C 10  aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl and wherein the substituents are selected from the group consisting of H, F, Cl, Br, I, (C 1 -C 6 )alkyl, —CN, —NO 2 . —OH, —O(C 1 -C 4 )alkyl), —S(C 1 -C 6 )alkyl), —S[(═O)(C 1 -C 6 )alkyl)], —S[(O 2 )(C 1 -C 6 )alkyl], —C[(═O)(C 1 -C 6 )alkyl], CF 3 , —O[(CO)—(C 1 -C 6 )alkyl)], —S(O 2 )[N(R 9 R 10 ), —NH[(C═O)(C 1 -C 6 )alkyl], —NH(C═O)N(R 9 R 10 ), and —N(R 9 R 10 ); wherein R 9  and R 10  are independently H or C 1 -C 6  alkyl) and Y is selected from the group consisting of —O—, —S—, —S—S—, —S(O)—, —S(O 2 )—, —NR 8 —, —C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)NH—, —NR 8 C(═O)—, —C(═O)NR 8 —, —NR 8 C(═O)NR 8 —, —NR 8 C(═O)NR 8 —, and —NR 8 C(═S)NR 8 .  
     
     
         24 . The composition of  claim 23 , except that each R 5  is —X—Y—.  
     
     
         25 . The composition of  claim 23 , comprising two molecules of the polymer, except that two of the four repeating units omit R 7  and are crosslinked to provide a single —R 5 —X—R 5 — conjugate, wherein X is selected from the group consisting of (C 1 -C 18 )alkyl, substituted alkyl, (C 3 -C 8 ) cycloalkyl, substituted cycloalkyl, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted heterocyclic, (C 2 -C 18 )alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 6  and C 10  aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl and wherein the substituents are selected from the group consisting of H, F, Cl, Br, I, (C 1 -C 6 )alkyl, —CN, —NO 2 . —OH, —O(C 1 -C 4 )alkyl), —S(C 1 -C 6 )alkyl), —S[(═O)(C 1 -C 6 )alkyl)], —S[(O 2 )(C 1 -C 6 )alkyl], —C[(═O)(C 1 -C 6 )alkyl], CF 3 , —O[(CO)—(C 1 -C 6 )alkyl)], —S(O 2 )[N(R 9 R 10 ), —NH[(C═O)(C 1 -C 6 )alkyl], —NH(C═O)N(R 9 R 10 ), and —N(R 9 R 10 ); wherein R 9  and R 10  are independently H or (C 1 -C 6 )alkyl.  
     
     
         26 . The composition of  claim 20 , except that two molecules of the polymer are partially crosslinked to provide an —R 5 —X—Y—R 7 —R 5 — conjugate.  
     
     
         27 . The composition of  claim 22 , except that one molecule of the polymer is covalently linked to the antigen through an —R 5 —R 7 —Y—X—R 5 — bridge (Formula XI):  
       
         
           
           
               
               
           
         
       
       wherein, X is selected from the group consisting of (C 1 -C 18 )alkylene, substituted alkylene, (C 3 -C 8 )cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted heterocyclic, (C 2 -C 18 )alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 6  and C 10  aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, wherein the substituents are selected from the group H, F, Cl, Br, I, (C 1 -C 6 )alkyl, —CN, —NO 2 . —OH, —O(C 1 -C 4 )alkyl, —S(C 1 -C 6 )alkyl, —S[(═O)(C 1 -C 6 )alkyl], —S[(O 2 )(C 1 -C 6 )alkyl], —C[(═O)(C 1 -C 6 )alkyl], CF 3 , —O[(CO)—(C 1 -C 6 )alkyl], —S(O 2 )[N(R 9 R 10 ), —NH[(C═O)(C 1 -C 6 )alkyl], —NH(C═O)N(R 9 R 10 ), —N(R 11 R 12 ), wherein R 9  and R 10  are independently H or (C 1 -C 6 )alkyl, R 11  and R 12  are independently (C 2 -C 20 )alkylene or (C 2 -C 20 )alkenylene.  
     
     
         28 . The composition of  claim 1 , wherein the peptidic antigen comprises a Class I epitope of about 8 to about 12 amino acids.  
     
     
         29 . The composition of  claim 28 , further comprising an adjuvant.  
     
     
         30 . The composition of  claim 29 , wherein the adjuvant is covalently bound to the polymer.  
     
     
         31 . The composition of  claim 29 , wherein the adjuvant and the antigen are conjugated to the same polymer.  
     
     
         32 . The composition of  claim 1 , wherein the peptidic antigen comprises a Class II epitope of about 8 to about 30 amino acids.  
     
     
         33 . The composition of  claim 1 , wherein the peptidic antigen comprises an epitope of a virus, bacterium, fungus or tumor cell surface antigen.  
     
     
         34 . The composition of  claim 33 , where the antigens are retro-inverso peptides.  
     
     
         35 . The composition of  claim 34 , where the antigens are partially retro-inverso peptides.  
     
     
         36 . The composition of  claim 1 , wherein the peptidic antigen comprises a viral epitope.  
     
     
         37 . The composition of  claim 36 , wherein the viral epitope is an HIV or influenza viral epitope.  
     
     
         38 . The composition of  claim 37 , wherein the HIV epitope has the amino acid sequence of SEQ ID NO: 8.  
     
     
         39 . The composition of  claim 37 , wherein the influenza epitope has the amino acid sequence of SEQ ID NO:9 or 10.  
     
     
         40 . The composition of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable vehicle.  
     
     
         41 . The composition of  claim 1 , wherein the composition is in the form of disperse droplets in a mist.  
     
     
         42 . The composition of  claim 41 , wherein the mist is produced by a nebulizer.  
     
     
         43 . The composition of  claim 1 , wherein the composition is contained within a nebulizer actuatable to produce a mist comprising dispersed droplets of the vehicle.  
     
     
         44 . The composition of  claim 1 , wherein the composition is contained within an injection device that is actuatable to administer the composition by injection.  
     
     
         45 . A method for inducing an immune response in a mammal, said method comprising: 
 administering to the mammal an immunostimulating amount of a vaccine delivery composition of  claim 1  in the form of a liquid dispersion of polymer particles or molecules, which are taken up by antigen presenting cells of the mammal to induce an immune response in the mammal.    
     
     
         46 . The method of  claim 45 , wherein the composition forms a time release polymer depot when administered in vivo.  
     
     
         47 . The method of  claim 45 , wherein the composition biodegrades over a period of twenty-four hours, about seven days, about thirty days, or about ninety days.  
     
     
         48 . The method of  claim 45 , wherein the composition is in the form of particles having an average diameter in the range from about 10 nanometers to about 1000 microns and the at least one peptidic antigen is dispersed in the particles.  
     
     
         49 . The method of  claim 45 , wherein the particles have an average diameter in the range from about 10 nanometers to about 10 microns.  
     
     
         50 . The method of  claim 45 , wherein the particles further comprise a covering of the polymer.  
     
     
         51 . The method of  claim 45 , wherein a particle includes from about 5 to about 150 peptidic antigens per polymer molecule.  
     
     
         52 . The method of  claim 45 , wherein a polymer molecule has an average molecular weight in range from about 5,000 to about 300,000 and the at least one peptidic antigen is conjugated to the polymer molecule.  
     
     
         53 . The method of  claim 45 , wherein a polymer molecule has from about 5 to about 70 peptidic antigens conjugated thereto.  
     
     
         54 . The method of  claim 45 , wherein the peptidic antigen comprises a Class I epitope of about 8 to about 12 amino acids.  
     
     
         55 . The method of  claim 45 , further comprising an adjuvant.  
     
     
         56 . The method of  claim 55 , wherein the adjuvant is covalently bound to the polymer.  
     
     
         57 . The method of  claim 55 , wherein the adjuvant and the antigen are conjugated to the same polymer.  
     
     
         58 . The method of  claim 45 , wherein the peptidic antigen comprises a Class II epitope of about 8 to about 30 amino acids.  
     
     
         59 . The method of  claim 58 , wherein the peptidic antigen comprises an epitope of a virus, bacterium, fungus or tumor cell surface antigen.  
     
     
         60 . A method for delivering a vaccine to a subject comprising administering to the subject a vaccine delivery composition of  claim 1  so that the vaccine is taken up by antigen presenting cells of the subject.  
     
     
         61 . A vaccine delivery composition comprising an effective amount of at least one MHC class I or class II peptidic antigen dispersed in a biodegradable polymer comprising at least one type of amino acid conjugated to at least one non-amino acid moiety per monomer.  
     
     
         62 . The composition of  claim 61 , wherein the non-amino acid moiety is between two adjacent amino acids.  
     
     
         63 . The composition of  claim 61 , wherein the non-amino acid moiety is hydrophobic.  
     
     
         64 . The composition of  claim 61 , wherein the peptidic antigen comprises from 5 to about 30 amino acids.  
     
     
         65 . The composition of  claim 61 , wherein the polymer comprises at least two different amino acids.  
     
     
         66 . The composition of  claim 61 , wherein the polymer is a block co-polymer that forms micelles in liquid.  
     
     
         67 . A method for inducing an immune response in a mammal, said method comprising: 
 administering to the mammal a vaccine delivery composition of  claim 61  in the form of a liquid dispersion of polymer particles or molecules, which are taken up by antigen presenting cells of the mammal to induce an immune response in the mammal.    
     
     
         68 . The composition of  claim 1 , wherein the R 3 s in at least one monomer further can be —(CH 2 ) 3 — and the at least one of the R 3 s cyclizes to form the chemical structure described by structural formula (XVIII):